nologic, and metabolic function (Chrousos and Gold, 1992). The HPA axis may be activated by stressful conditions with specific behavioral phenotypes (anxiety, major affective disorders); conversely, there is evidence that administration of components of the axis, such as CRH, glucocorticoids, and POMC products, modulates behavior.

RU 486 AS AN ANTIGLUCOCORTICOID

RU 486 represents the first clinically active glucocorticoid antagonist, and has been used to probe glucocorticoid action and to treat conditions known or suspected to be glucocorticoid sensitive or dependent. The remainder of this paper reviews these studies, and concludes with speculations about other potential uses and further studies to be performed.

The antiglucocorticoid activity of RU 486 was first demonstrated in women undergoing induced abortion (Herrmann et al., 1982) and in normal men in acute dose-response studies using ACTH/lipotropin (LPH) and cortisol levels as end points (Bertagna et al., 1984; Gaillard et al., 1984). The rationale of this experimental design is that interruption of glucocorticoid negative feedback should increase CRH, ACTH, and eventually cortisol secretion to overcome RU 486 inhibition. A consistent dose-response relationship emerged: RU 486, at daily doses of 3–6 mg/kg given for one to four days, caused a dose-dependent increase in pituitary or cortisol end points. The effect at 3 mg/kg was transient and was not observed at lower doses. Interestingly, regardless of the time of administration of RU 486 (morning versus evening), the hormonal effect was observed only in morning values, so that the diurnal rhythm was maintained and amplified. The ability of dexamethasone, 1 mg at midnight, to suppress morning cortisol values was completely antagonized by RU 486, 6 mg/kg. Although the apparent "resistance" of the HPA axis to RU 486 effects during the evening hours (8:00 p.m.–2:00 a.m.) remains unexplained, the persistence of a demonstrable effect 24 hours after morning administration of RU 486 may be explained in part by its long plasma half-life of around 20 hours.

Patients with Cushing's syndrome, studied in a similar way by using ACTH and cortisol as response measures, had different responses depending on the etiology of Cushing's syndrome. Patients with Cushing's disease, in whom an ACTH-producing pituitary tumor retains many of the normal physiologic regulatory mechanisms, responded to RU 486 with increased cortisol levels. By contrast, patients with other causes of Cushing's syndrome (in whom hypercortisolism presumably suppressed activity of normal ACTH-producing pituitary corticotropes) showed no response to RU 486 (Bertagna et al., 1986).

In principle, administration of a glucocorticoid antagonist would



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